Drugs currently known as calcium channel blockers (CCB) (also called calcium antagonists), among other actions, inhibit calcium-evoked contractions in depolarized smooth muscles. Blocking the entry of calcium reduces the active tone of vascular smooth muscle and produces vasodilatation. This pharmacological property has, at a minimum, been one of the bases for the use of CCBs in the management of hypertension and coronary heart disease. CCBs may have other effects that help prevent the primary complications of hypertension, such as atherosclerosis, stroke, peripheral arterial disease, heart failure and end-state renal disease. CCBs are prescribed for the treatment and/or prophylaxis of vasospastic angina, including spontaneous coronary artery spasm presenting as Prinzmetal's angina, chronic stable angina, unstable angina, arrhythmias, such as arrhythmias associated with digitalis therapy, and arrhythmias associated with stress in chronic arterial flutter or arterial fibrillation, supraventricular tachyrrhythmias, paroxysmal supraventricular tachycardia, and subarachnoid hemorrhage. In addition, CCBs are prescribed for treatment and/or prevention of reinfarction of non-Q-wave myocardial infarction, tardive dyskinesia, Raynaud's syndrome, coronary heart disease, migraine, pulmonary hypertension, asthma, preterm labor, severe pregnancy-associated hypertension, esophageal disorders, biliary and renal colic, cardiomyopathy, coronary artery disease, and depression. As a class, CCBs represent an important and useful tool in pharmacotherapy.
Many CCBs can be divided into three categories based on their chemical structure; these three categories are diphenylalkylamines, benzothiazepines, and dihydropyridines.
With respect to the diphenylalkylamines, verapamil (described in U.S. Pat. No. 3,261,859) is one member of this category of CCBs, along with 2-(3,4-dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethyl-methyl-amino]-2-(1-methylethyl)pentanenitrile, the structure of which is shown immediately below.

2-(3,4-dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethyl-methyl-amino]-2-(1-methylethyl)pentanenitrile
With respect to benzothiazepines, diltiazem (described in U.S. Pat. No. 3,562,257) is one member of this category of CCBs. The chemical name of diltiazem is [2-(2-dimethylaminoethyl)-5-(4-methoxyphenyl)-3-oxo-6-thia-2-azabicyclo[5.4.0]undeca-7,9,11-trien-4-yl]ethanoate. The structure of diltiazem is shown immediately below.

With respect to the dihydropyridines, amlodipine (described in U.S. Pat. No. 4,572,909), felodipine (described in U.S. Pat. No. 4,264,611), isradipine (described in U.S. Pat. No. 4,466,972), nicardipine (described in U.S. Pat. No. 3,985,758), nifedipine (described in U.S. Pat. No. 3,485,847), nimodipine (described in U.S. Pat. No. 4,406,906), and nisoldipine (described in U.S. Pat. No. 4,154,839) are each members of this category of CCBs. The structure of each of the aforementioned dihydropyridines is shown immediately below.

Although not easily placed within any of the three previously mentioned categories of CCB's, bepridil (described in U.S. Pat. No. 3,962,238 and RE 30,577) is another CCB. The structure of bepridil is shown immediately below

Although CCBs serve an important role in treating patients, their use is sometimes associated with (among other things) extensive metabolism, often resulting in inactive metabolites and thus lower bioavailability. CCBs also exhibit several side effects of the cardiovascular and central nervous systems, as well as dermatologic, gastrointestinal, and hematological adverse effects. Research is ongoing to improve the bioavailability of CCBs and to reduce side effects associated with CCB therapy. Thus, there is a need to provide CCBs with improved pharmacological properties.
The present invention seeks to address these and other needs in the art by providing (among other things) a conjugate of a water-soluble and non-peptidic oligomer and calcium channel blocker.